1. Field of the Invention
This invention relates to novel antibacterial agents; namely, (substituted acyl)derivatives of .alpha.-aminoacyl penicillins. More particularly, it is directed to 6-[.alpha.-(.omega.-guanidinoalkanoylamido)acylamido]penicillanic acids, the non-toxic salts and esters thereof, which are especially useful in the treatment of gram-negative infections and, particularly, Pseudomonas infections.
2. Description of the Prior Art
A large number of 6-(.alpha.-aminoacylamido)penicillanic acids wherein the acyl moiety is alkanoyl or substituted alkanoyl wherein the substituent is an aryl, cycloalkyl or heterocyclic group are disclosed in U.S. Pat. Nos. 2,985,648, 3,007,920; 3,192,198; 3,485,819; 3,342,677; 3,538,083; 3,553,201; British Pat. Nos. 873,049; 903,785; 991,586; 1,033,257 and 1,189,990. Further, 6-[.alpha.-substituted amino)acylamido]penicillanic acids are described in U.S. Pat. Nos. 3,198,788; 3,248,387; 3,308,023; 3,320,240; 3,325,477; 3,340,252; 3,381,001; 3,433,784; 3,518,253; British Pat. Nos. 891,977; 894,457; 985,688; 1,048,907 1,051,675; 1,057,697; 1,064,893; 1,066,107; 1,125,339; 1,180,745; 1,210,472; Belgian Pat. No. 593,295 and Japanese Pat. No. 7,116,994. Additionally, 6-(.alpha.-ureido acylamido)penicillanic acids are disclosed in U.S. Pat. No. 3,352,851 and German Pat. No. 2,054,772; 6-(.alpha.-guanidinoacylamido)penicillanic acids in U.S. Pat. No. 3,454,557 and 3,406,185; and a variety of p-guanidinoaroyl-, p-guanidinomethylaroyl- and p-guanidinoarylalkanoylamidopenicillanic acids are disclosed in U.S. Pat. No. 3,453,265. British Pat. No. 1,061,335 discloses 6-(D-.alpha.-hydrazinocarbonylamino-.alpha.-phenylacetamido)penicillanic acid, and British Pat. No. 1,053,818 describes esters of 6-(.alpha.-oxalamidoacylamido)penicillanic acids.
A wide variety of 6-[.alpha.-(3-substituted ureido)acylamido]penicillanic acids and 6-[.alpha.-(3-substituted thioureido)acylamido]penicillanic acids are reported in the recent literature. U.S. Pat. Nos. 3,479,339; 3,481,922; Netherlands Pat. Nos. 69,01646; 69,08909; and Japanese Pat. No. 7,112,732 describe such compounds wherein the 3-substituent is a carbamoyl group; the compounds being referred to as 6-[.alpha.-(3-allophanamido)acylamido]penicillanic acids. U.S. Pat. No. 3,579,501 discloses 6-[.alpha.-(3-guanylureido)acylamido]penicillanic acids; that is, such compounds wherein the 3-substituent is a guanyl moiety.
The above described products are active as antibacterial agents against a variety of gram-positive and gram-negative bacteria. However, while they are active in vitro and in vivo via the intraperitoneal route of administration, they are inactive or, at best, poorly active in vivo via the oral route of administration. Additionally, their pharmaco-kinetics, as evidenced by levels of the compound in the blood, are poor.